Cardiovascular disease, specifically sudden cardiac death represents the most common cause of death among methamphetamine (METH) users but precise mechanism is unknown. Preliminary data in this proposal using a novel small animal electrophysiology set up shows that METH infusion in mice decreases atrial and ventricular hydrogen sulfide (H2S) levels and increases inducible atrial and ventricular arrhythmias. This proposal tests the hypothesis that METH use enhances reactive oxygen species production in the heart through altered H2S production, resulting in structural and electrical remodeling in the atria and ventricles of the heart leading to atrial and ventricular arrhythmias. To achieve this long-term objective, the role of H2S in METH associated electrical and structural remodeling in the heart will be evaluated by analyzing arrhythmia phenotype, action potential duration and fibrosis in METH infused Cystathionine ?-lyase (CSE, the predominant enzyme responsible for H2S production in mammals)transgenic mice and wild type (WT) mice supplemented with sulfide, compared to WT mice. In addition, the effect of oxidative stress in METH-associated electrical and structural remodeling in the heart will be assessed by measuring tissue and mitochondrial super-oxide levels in the atria and ventricles of METH and saline treated mice and by measuring the effect of METH on the arrhythmia phenotype and structural and electrical remodeling in pharmacological and genetic mouse models of oxidant stress inhibition. Furthermore, the role of calcium calmodulin kinase II (CaMKII) and Ryanodine receptor (RyR2) on METH induced oxidative stress mediated cardiac arrhythmias will be evaluated by measuring phosphorylated and oxidized CaMKII and RyR2 in the heart tissue of METH and saline treated WT mice, CSE-Tg mice and pharmacological and genetic mouse models of oxidant stress inhibition. Finally, the relationship between METH use, resultant catecholamine levels, H2S bioavailability, oxidative stress, psychological and cognitive dysfunction and cardiac arrhythmias will be evaluated by correlating cardiac arrhythmias to H2S levels, and scores on behavioral tests in METH and saline treated WT and CSE Tg mice.